Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
  • A61K33/10—Carbonates; Bicarbonates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
  • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to the field of pharmaceutical formulation science, in particular with respect to methods of improving a process for production of calcium containing particulate material.
• Particulate matter or a granular material may be produced by a variety of production processes in pharmaceutical manufacture including high speed mixing, dry granulation or compaction, extrusion and fluid bed processing.
• the most common method of granulation in pharmaceutical manufacture is by high speed mixing or high shear mixing and subsequent drying of the moist granulate in a fluid bed. This method produces a dense granulate which is appropriate for making small tablets with a high density. Fluid bed granulation is much less used as this is a more complicated process and more costly with respect to investment, process validation and running cost.
• the fluid bed granulation process produces a less dense granulate, which may be undesirable when ordinary tablets to be swallowed are to be manufactured.
• the use for calcium chewable products demands very specialized raw materials and most important a very delicate production process. The importance of combining critical characteristics of the raw materials together with a carefully selected production process has been shown for calcium chewable tablets in EP-A-1 128 815 of Nycomed Pharma AS.
• This document describes a process by which the undesirably high bulk of a chewable tablet containing calcium carbonate is reduced.
• the reduced tablet size has been accomplished by careful selection of the physical properties of the calcium carbonate source and a fluid bed granulation and drying process.
• the optimal windows for the mean particle size and specific surface area were found to be 3 to 40 ⁇ m and 0.1 to 1.2 m 2 /g respectively for the preferred qualities of calcium carbonate.
• the choice of particle size range was especially important in order to achieve a satisfactory chewability and dispersion in the mouth where as the specific surface area was important in order to accomplish an efficient or short processing time during the granulation and drying phase in a fluid bed.
• the fluid bed granulation step has resulted in a very homogenous distribution of the binder, which in turn results in a rapid dispersion of the table when chewed but also very good consolidation properties during the tableting step. This last property is very important for the productivity of high speed tableting machines to ensure maximum output and a minimum demand for cleaning and maintenance of tablet tooling.
• the in-process sampling procedure for a batch fluid bed is a problem due to the fact that the calcium granulates as it comes out of the product container may not be homogenous with respect to the moisture content and particle size distribution. This is especially the case when there has been a problem with too humid conditions in the fluid bed with a resultant insufficient drying and lump formation.
• the process is a batch process where the raw material must be loaded and removed after each batch, slowing down the production rate considerably.
• Continuous fluid bed granulation and drying is mainly a process that has been utilized for high volume or mono-product processes in chemical and food industry.
• the pharmaceutical industry has not utilized this technology to any great extent due to fact that pharmaceutical production normally requires rapid batch and recipe changes, a rigorous cleaning between product changes and regulatory difficulties in the definition of batch size.
• the mean particle size can be effectively varied over a wide particle size range in the continuous fluid bed process by carefully controlling the moisture load, which the powder mixture is exposed to.
• the continuous fluid bed process is much less sensitive to processing difficulties and variation in moisture content and particle size/distribution of the granulate when different sources of calcium are employed with different physical characteristics like specific surface area, particle size/distribution and particle shape.
• it has been found that it is possible to obtain a much narrower particle size distribution by using a process involving continuous fluid bed than by a process using batch fluid bed.
• Such a narrow particle size distribution is of particular advantage in order to obtain homogeneous powder mixtures.
• the present invention relates to a process for producing a particulate material comprising a calcium-containing compound, the process comprises granulating a fluidized composition comprising the calcium-containing compound optionally together with one or more pharmaceutically acceptable excipients under fluidizing conditions in a continuous fluid bed apparatus.
• the present method has been found to be an efficient and cost-effective method that, furthermore, has the advantages that a particulate material is prepared that has controllable moisture content that has controllable particle size and particle size distribution. Moreover, the method is a robust process, which means that once the process parameters for the fluid bed process are found and the fluid bed process is started, no or only minor adjustments are required.
• the process of the invention comprises the steps of
• the particulate material normally has a content of calcium compound of at least about 40 % by weight, normally at least about 60% w/w such as at least about 70% w/w, at least about 80% w/w, at least about 90% w/w or at least about 95% w/w.
• the method may comprise a step of compressing the particulate material obtained optionally together with one or more pharmaceutically acceptable excipients and/or one or more therapeutically, prophylactically and/or diagnostically active substance to form tablets.
• the invention relates to a particulate material comprising a calcium- containing compound and one or more pharmaceutically acceptable excipients, wherein the SPAN value is at the most about 2.3 such as, e.g., at the most about 2.25, at the most about 2.1 , at the most about 2 or at the most about 1.9.
• a span value in the range of from about 1.7 to about 1.9 is obtainable by the process according to the invention, while the span value obtained relating to the preparation of a particulate material having the same composition but using a batch fluid bed process results in a span value of about 2.6-2.7. Accordingly, shift from a batch fluid bed to a continuous fluid bed decreases the span value about 30%.
• the SPAN value is calculated as [D(v, 0.9) - D(v, 0.1)]/D(v, 0.5),
• the particle size analysis is performed on a Malvern Mastersizer S long bench apparatus where D(v, 0.1), D(v, 0.5) and D(v, 0.9) give the particle sizes for which 10%, 50% and 90% of the particles by volume have sizes below the given values.
• D(v, 0.5) is the mean particle size.
• a continuous fluid bed process according to the invention results in particulate material that has a very narrow particle size distribution as evidenced by the span value.
• the invention relates to the use of a particulate material as defined herein or obtained by a process as defined herein for the preparation of a dosage form.
• the invention relates to a process for producing a solid dosage form comprising a calcium-containing compound, said process comprises steps of i) optionally mixing a particulate material obtained as defined herein with one or more pharmaceutically acceptable excipients to produce a powder mixture that has a content of the calcium-containing compound of at least 60 % by weight; and ii) processing the particulate material or the powder mixture into the solid dosage form.
• a batch fluid bed is based on the principle that four distinct unit-process phases take place in one and the same compartment, namely preheating/mixing, granulation, drying and cooling.
• the set-points for the critical process parameters will have to be changed frequently in order to carry out a batch recipe.
• All in all the batch process requires a thorough control and monitoring of the process to ensure that the critical process parameters are within the validated process windows at all times. This is due to the fact that the batch process requires frequent stepwise adjustments of the critical process parameters as the batch recipe is carried out.
• the process parameters employed during the preheating/mixing step are different from those employed in the granulation step that again are different from those employed in the drying step and in the cooling step.
• each process step takes place with its own inlet air compartment or zones, which may be a more proper term, as the individual zones may not be strictly separated from each other.
• FIG 1 shows a continuous fluid bed apparatus having four inlet air compartments, in this case two granulation zones and one drying and one cooling zone.
• the inlet air of each zone can be individually controlled with respect to the air volume, absolute moisture content and temperature, which ensures that these critical process parameters are not subject to any changes during the whole process - the one and same zone has the same function, i.e. carries out a particular unit-process during the whole process and accordingly, there is no need for adjusting any process parameter to another unit- process. Accordingly, all critical process parameters remain unchanged during the continuous process.
• the continuous fluid bed process is a steady state process, which means that at any point in the horizontal fluidized bed there will be stationary conditions. This gives a much better process control than a batch process, as it is not necessary to adjust the critical process parameters in each compartment. This results in fewer fluctuations of the critical process parameters and a better process control. Furthermore, a continuous fluid bed has both a much lower bed height and a lower amount of product per m 2 of product screen compared to a batch process. This allows for more fluidization air per kg product and gives more flexibility with respect to adjusting the moisture load and drying conditions. The result is a more controlled fluidization with much less chance of uncontrolled agglomeration and uneven wetting of the powder bed.
• the present inventors have found that use of continuous fluid bed apparatus solves most of the problems with adherence of the granulate to the inner parts of fluid bed apparatus, uncontrolled lump formation at high relative humidity in the product container and inhomogeneous sampling of particulate material.
• the use of a continuous fluid bed apparatus also reduces the time-consuming loading/unloading process and in particular minimizes the need for cleaning.
• Another advantage of using continuous fluid bed apparatus is that the mean particle size can be effectively varied over a wide particle size range in the continuous fluid bed process by carefully controlling the moisture load that the powder mixture is exposed to.
• the in-process sampling is well controlled in a continuous process as a sample is taken out of the continuous and homogenous product stream on the outlet side.
• the continuous fluid bed process thus offers a better process control and a more reproducible process with fewer variations in product characteristics like bulk density, particle size/distribution and moisture content when compared to a batch process.
• the present invention relates to a process for producing a particulate material comprising a calcium-containing compound, the process comprises granulating a fluidized composition comprising the calcium-containing compound optionally together with one or more pharmaceutically acceptable excipients under fluidizing conditions in a continuous fluid bed apparatus.
• Figure 1 is shown a schematic drawing of a continuous fluid bed apparatus. As seen from the figure, the composition is fed into the apparatus and the individual unit- processes takes place in zones within the continuous fluid bed. Accordingly, a process according to the invention comprises the steps of
• cooling may also be applied to the dried composition before it is collected.
• steps i) and iv) and/or steps iii) and iv) are performed in different zones of the continuous fluid bed apparatus.
• the present invention discloses a process as described above, whereby adherence of the processed material to inner parts of the continuous fluid bed apparatus is substantially avoided.
• the present invention discloses a process as described above whereby the particulate material obtained is a free-flowing, non-adherent particulate material.
• the low moisture content corresponds to a range of from about 0.1 % to about 0.5% w/w such as, e.g., from about 0.1% to about 0.3%.
• the following is a description of the critical process parameters for a continuous fluid bed process and in particular the typical processing windows for the critical process parameters for the granulation of a calcium-containing compound in a range of continuous fluid bed models with different capacities or outputs.
• the feed rate of the calcium-containing composition applied to the process will depend on the particular apparatus used as laid down in the table below. The specific values stated below are based on the preparation of a specific particulate material as described in the examples herein.
• composition of the particular particulate material to be prepared and the desired mean particle size e.g. the feed rate, the spray load, the air flow and the bed load may be varied within certain limits such as e.g. ⁇ 50%, ⁇ 40%, ⁇ 30%, ⁇ 20% or ⁇ 10%.
• the production scale equipment as laid down in the above table is from Heinen and it must be understood that the same processing conditions and relationships will apply to other types of continuous fluid bed granulation and drying equipment from suppliers like Glatt and Niro/Aeromatic.
• the table gives the relationship between the critical process parameters for a particular product in a continuous fluid bed with the following definitions:
• Product screen area (m 2 ) It is the specific fluid bed area (m 2 /kg/h), which is important when scaling up or down in a continuous fluid bed. The value should be constant for each individual processing section (agglomeration, drying and cooling).
• Feed rate (kg/hr): This is proportional to the output and denotes the production capacity for a given production scale equipment.
• Bed load (kg): This denotes the actual amount of material inside the equipment at any moment.
• Spray load (g H 2 O/min): This is the amount of pure water (or solvent) sprayed on to the moving bed when corrected for the dry material in the added binder.
• Airflow (m 3 /hr): This is the total volume of air going through the sum of the process compartments in the processing equipment.
• Linear air velocity (m/s): This is air speed, which the fluidised powder bed experience at the bottom of the product container near the bottom screen.
• the spray load is chosen such as to give a granulate with optimal granule characteristics with respect to particle size/distribution, bulk density and moisture content.
• Retention time (hr): This is defined as bed load over feed rate.
• continuous fluid bed process is intended to mean a process, wherein each unit-process phase takes place with its own inlet air compartment. This is visualised in figure 1 by one or two granulation, one drying and one cooling compartment.
• the inlet air of each compartment can be individually controlled with respect to the absolute moisture content and temperature, which ensures that these critical process parameters can stay unchanged during the continuous process.
• pillate material is intended to be synonymous with granulate material or simply granulate.
• formulated is intended to relate to the selection of excipients, carriers, vehicles, solvents, co-solvents, preservatives, colouring agents, flavouring agents and so forth in the preparation of a medicament using said composition.
• pharmaceutically acceptable excipient is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se.
• a pharmaceutically acceptable excipient may be added to the active drug substance with the purpose of making it possible to obtain a pharmaceutical formulation, which has acceptable technical properties.
• set-point processing parameters are important to adjust properly e.g. when changing composition of the particulate material to be prepared or in connection with e.g. up- or down-scaling between different continuous fluid bed equipment sizes: i) air velocity, ii) inlet air temperature, iii) inlet air humidity, iv) bed height, v) feed rate (kg/h)/spray load (kg solvent/h), vi) atomizing pressure for the nozzle(s) employed, vii) number of nozzles/product screen area.
• up- and down-scaling is used to denote a shift in apparatus size and not just an increase or decrease in the bed load of a particular apparatus.
• the most important parameter to keep constant is the ratio between the feed rate (kg/h) and the spray load (kg solvent/h).
• two or more such as, e.g., 3 or more, 4 or more, 5 or more, 6 or more or all s of the set-point processing parameters are kept constant during up- or down-scaling.
• the process according to the invention is relatively robust with respect to set-point processing parameters towards changes in the mean particle size of the particular calcium-containing compound employed.
• WT4/13 continuous fluid bed apparatus consists of a sieve bottom plate of about 0.52 m 2 and with three inlet air sections that can be controlled separately with respect to air volume, temperature and humidity.
• the equipment has a capacity in the range of up to 100 kg agglomerated product per hour, an air throughput of maximum 1800 m 3 /h and a water evaporation rate of maximum 70 kg/h.
• the three spray nozzles were positioned after each other above the fluidised bed (top spray) in the centre of the bed where the first nozzle sprayed at an angle against the direction of the moving bed and the two next nozzles at an angle with the moving bed. Two nozzles were positioned in the first compartment whereas the third nozzle was positioned in the second compartment.
• Figure 2 shows a photograph of WT4/13.
• the trials showed an index of feed rate/spray load in a range of 4.5 to 45, such as, e.g. from about 5 to about 40, from about 5 to about 35, from about 5 to about 30, from about 5 to about 25, from about 6 to about 20, from about 6 to about 15, from about 6 to about 10 or from about 7 to about 8.
• an index of feed rate/spray load in a range of 4.5 to 45, such as, e.g. from about 5 to about 40, from about 5 to about 35, from about 5 to about 30, from about 5 to about 25, from about 6 to about 20, from about 6 to about 15, from about 6 to about 10 or from about 7 to about 8.
• 4.5 to 45 such as, e.g. from about 5 to about 40, from about 5 to about 35, from about 5 to about 30, from about 5 to about 25, from about 6 to about 20, from about 6 to about 15, from about 6 to about 10 or from about 7 to about 8.
• the ingredients fed to the first zone are normally in the form of a composition comprising one or more calcium-containing compounds.
• the composition may be exclusively composed of one or more calcium-containing compounds, in particular of one calcium-containing compound, or it may be composed of a mixture of the calcium- containing compound(s), one or more pharmaceutically acceptable excipients and, if relevant, one or more therapeutically, prophylactically or diagnostically active substances such as, e.g., those mentioned herein.
• the pharmaceutically acceptable excipients are materials normally employed such as, e.g. fillers, diluents etc. Specific examples can be found under the heading "Pharmaceutically acceptable excipients" and in the examples herein.
• the particulate material obtained by a method according to the invention comprises i) one or more calcium-containing compounds, ii) one or more binders iii) optionally, one or more pharmaceutically acceptable excipients iv) optionally, one or more sweetening agents.
• the one or more pharmaceutically acceptable excipients and/or sweetening agents are contained in the composition containing the calcium-containing compound that is granulated in the continuous fluid bed.
• the binder may also be present in this composition.
• the particulate material comprises i) from about 40% to about 99.9% w/w of one or more calcium containing compounds, ii) from about 0.1 % to about 30% w/w of one or more binders iii) from about 0.1 to about 15% w/w of one or more pharmaceutically acceptable excipients, if present, and iv) from about 5% to about 50% w/w of one or more sweetening agents, if present, provided that the total concentration does not exceed 100%.
• the feed rate depends on the size of the product screen area of the continuous fluid bed apparatus.
• the feed rate is normally in a range from 25 to 200 kg/h, such as e.g. 50 to 100 kg/h, in particular 60 to 80 kg/h and preferably about 75 kg/h for an apparatus with a bed load of about 75 kg.
• the retention time is one hour with a resultant bed load of 75 kg.
• the feed rate may be much higher, e.g. from about 500 to about 1000 kg/h when larger equipment sizes are employed.
• the ratio between the feed rate (kg/h) of the composition comprising the calcium-containing compound and the spray load (kg solvent/h) of the granulation liquid is important in order to obtain the desired product.
• the ratio is in a range of from about 4 to about 45 such as, e.g., in a range of from about 6 to about 23, from about 6 to about 12, from about 6 to about 10, from about 6.5 to about 8.5 or from about 7 to about 8.
• Granulation takes place in the first two zones with position of the nozzles as described above
• the number of nozzles may vary, cf. above.
• three nozzles are used and they are positioned above the pulsating powder bed to deliver a fine atomised spray with the granulation liquid (which in a specific embodiment contains the dissolved binder) with a resulting agglomeration of particles to form larger granules or agglomerates.
• the granulation of the fluidized composition is performed by means of a granulation liquid that is applied to the fluidized composition comprising the calcium-containing compound.
• the granulation liquid comprises a pharmaceutically acceptable binder.
• suitable agglomeration may also be obtained by application of the granulation liquid to a fluidized composition that comprises a pharmaceutically acceptable binder.
• the composition comprises e.g. a sugar alcohol that has binding properties.
• a binder in the granulation liquid as well as in the fluidized composition.
• the granulation liquid may also contain one or more further pharmaceutically acceptable excipients or additive such as, e.g., soluble or intense sweeteners.
• the granulation liquid is normally based on water although organic solvents like e.g. alcohol (e.g. ethanol, propanol or isopropanol) may be added.
• organic solvents like e.g. alcohol (e.g. ethanol, propanol or isopropanol) may be added.
• the binder is selected from water-soluble binders.
• binders examples include dextrins, maltodextrins (e.g. Lodex® 5 and Lodex® 10), dextrose, fructose, glucose, inositol, erythritol, isomalt, lactitol, lactose (e.g., spray- dried lactose, ⁇ -lactose, ⁇ -lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast-Floe®), maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, low-substituted hydroxypropylcellulose (e.g LH 11 , LH 20, LH 21 , LH 22, LH 30, LH 31 , LH 32 available from Shin-Etsu Chemical Co.), microcrystalline cellulose (e.g., various grades of Avicel®, such as Avi
• polyvinylpyrrolidone polyvinylpyrrolidone/vinyl acetate copolymer
• agar e.g. sodium alginate
• carboxyalkylcellulose e.g. sodium alginate
• dextrates e.g. dextrates
• gelatine gummi arabicum
• hydroxypropyl cellulose hydroxypropylmethylcellulose
• methylcellulose polyethylene glycol, polyethylene oxide
• polysaccharides e.g. dextran, soy polysaccharide.
• the granulation liquid is an aqueous medium.
• the granulation liquid is prepared by dissolving or dispersing the binder in water.
• the binder can be admixed in a dry form to the powder. The present inventors have found that the spray rate or more correctly the spray load of the granulation liquid has a major impact on the mean particle size, whereas the inlet temperature and binder concentration in the granulation liquid have minor effect on particle size. The subsequent drying and, if needed, cooling steps have little influence on the mean particle size.
• the invention provides a method for controlling the mean particle size of the particulate material obtained by a process according to the present invention by proper adjustment of the spray load and/or the moisture content of inlet air.
• the particle size increases with increasing spray load (if an aqueous medium is used in the granulation liquid) or with increasing moisture content of the inlet air (see e.g. the examples herein).
• a particulate material obtained by a process according to the invention has a mean particle size that is suitable for use within the pharmaceutical field especially in connection with further processing of the particulate material into a solid dosage form.
• the mean particle size of the particulate material obtained is normally in a range of from about 100 to about 500 ⁇ m such as, e.g., from about 100 to about 400 ⁇ m, from about 100 to about 350 ⁇ m or from about 100 to about 300 ⁇ m.
• the present invention relates to a process, wherein a very narrow size distribution of the particulate material is obtained.
• a narrow size distribution is important in order to secure an acceptable homogeneity when the particulate material is mixed with other solid pharmaceutically acceptable excipient e.g. for the manufacture of solid dosage forms.
• a suitable homogeneity ensures that the correct dose is contained in each dosage form, thus, enabling fulfilling of the official requirements with respect to e.g. dose variation.
• a mean particle size which coincides with the mean particle size and particle size distribution of vitamin D 3 has been found to be important in order to ensure a satisfactory homogeneity of vitamin D 3 in the particulate material or the tableting end-mix.
• a narrow distribution for the particle size is characterised by a low value for the span value as defined below.
• the SPAN value is calculated as [D(v, 0.9) - D(v, 0.1)]/D(v, 0.5),
• the particle size analysis is performed on a Malvern Mastersizer S long bench apparatus where D(v, 0.1), D(v, 0.5) and D(v, 0.9) give the particle sizes for which 10%, 50% and 90% of the particles by volume have sizes below the given values.
• D(v, 0.5) is the mean particle size.
• the span value is at the most about 2.3 such as, e.g., at the most about 2.25, at the most about 2.1 , at the most about 2 or at the most 1.9.
• a narrow particle size distribution can be obtained irrespective of the kind and size of the continuous fluid bed apparatus employed, and/or the particular calcium carbonate employed.
• the particulate material obtained normally has a SPAN value of at the most about 2.3 such as, e.g., at the most about 2.25, at the most about 2.1 or at the most about 2 irrespective of the bed size of the continuous fluid bed apparatus employed, provided that the composition of the particular particulate material is the same and the ratio between the feed rate (kg/h) and the spray load (kg/h) is kept substantially constant, and/or the particulate material obtained has a SPAN value of at the most about 2.3 such as, e.g., at the most about 2.25, at the most about 2.1 or at the most about 2 irrespective of the particle size of the particular calcium-containing compound employed provided that all other conditions including the set-points for processing parameters are substantially identical, and/or the particulate material obtained has a SPAN value of at the most about 2.3 such as, e.g., at the most about 2.25, at the most about 2.1 or at the most about 2 irrespective of the bulk density of the particular calcium-containing compound employed provided all other conditions
• the granulated composition obtained under by a process according to the invention has a SPAN value that is smaller than that obtained when granulating the same composition with the same granulation liquid, but in a batch fluid bed apparatus.
• the SPAN value obtained is about 10% or more such as, e.g., about 15% or more, about 20% or more or about 30% or more smaller than that obtained using a batch fluid bed apparatus.
• a critical parameter is the moisture load which the powder mixture is exposed to from the spray nozzles where the granulation liquid optionally containing an acceptable binder.
• a process according to the invention is illustrated by the preparation of a particulate material containing a calcium-containing compound, wherein the calcium- containing compound in admixture with one or more pharmaceutically acceptable excipients is granulated with an aqueous solution of polyvinylpyrrolidone as an example of a binder.
• the concentration of the pharmaceutically acceptable binder in the dispersion, preferably a solution that is sprayed onto the powder mixture is at the most about 50% w/w such as at the most about 33% w/w.
• Drying takes place normally in another zone than that used for application of the granulation liquid. During drying the moisture inside the granules is evaporated by the aid of diffusion. It is favourable to practice a high inlet temperature in order to ensure a quick drying process with a resultant low moisture content below 0.5% in the outlet granular material.
• the drying inlet air is in the range of 45 to 10O 0 C and more preferably 70 to 100 0 C.
• the invention also relates to a particulate material comprising a calcium-containing compound and one or more pharmaceutically acceptable excipients, wherein the SPAN value is at the most about 2.3 such as, e.g., at the most about 2.25, at the most about 2.1 or at the most about 2.
• the particulate material can be prepared by the process as claimed herein, preferably it is prepared in this manner.
• the particulate material has a mean particle size in a range of from about 100 to about 500 ⁇ m such as, e.g., from about 100 to about 400 ⁇ m, from about 100 to about 350 ⁇ m or from about 100 to about 300 ⁇ m.
• the particulate material of the present invention comprises i) one or more calcium containing compounds, ii) one or more binders iii) optionally, one or more pharmaceutically acceptable excipients iv) optionally, one or more sweetening agents.
• the particulate material comprises i) from about 40% to about 99.9% w/w of one or more calcium containing compounds, ii) from about 0.1% to about 30% w/w of one or more binders iii) from about 0.1 to about 15% w/w of one or more pharmaceutically acceptable excipients, if present, and iv) from about 5% to about 50% w/w of one or more sweetening agents, if present, provided that the total concentration does not exceed 100%.
• the invention relates to the use of a particulate material as defined herein or obtained by a process as defined herein for the preparation of a dosage form.
• a particulate material as defined herein or obtained by a process as defined herein for the preparation of a dosage form.
• a particulate material together with a vitamin D containing composition for the preparation of a dosage form.
• the invention relates to a process for producing a solid dosage form comprising a calcium-containing compound, said process comprises steps of i) optionally mixing a particulate material obtained as defined herein with one or more pharmaceutically acceptable excipients to produce a powder mixture that has a content of the calcium-containing compound of at least 60 % by weight; and ii) processing the particulate material or the powder mixture into the solid dosage form.
• the present invention provides a process for producing a pharmaceutically acceptable dosage form, said process comprises steps of i) optionally mixing the particulate material obtained by employing of the continuous fluid bed process according to the present invention with one or more further components, i.e.
• a second particulate material preferably having a content of calcium compound of at least 60 % by weight; and ii) optionally compressing said first or second particulate material to form tablets.
• said further component mixed with the particulate material obtained from the continuous fluid bed process is a therapeutically, prophylactically and/or diagnostically active agent.
• said further component mixed with the particulate material obtained from the continuous fluid bed process is Vitamin D.
• said further component mixed with the particulate material obtained from the continuous fluid bed process is Vitamin D 3 or Vitamin D 2 or derivatives thereof, or mixtures thereof.
• the present invention discloses a process as described above, wherein the homogeneity of the further component such as Vitamin D 3 is very high in both the particulate material used to compress tablets (i.e. in the admixture of the particulate material obtained from the continuous fluid bed process and the one or more further components) and the resulting tablets.
• the resulting particulate material i.e. the material used for the compression
• a suitable solid dosage form is tablets, capsules or sachets including chewable, suckable and swallowable tablets.
• the solid dosage form is in the form of tablets that optionally are provided with a coating. All details and particulars mentioned under the main aspect of the invention (process for preparing a particulate material) apply mutatis mutandis to the other aspects of the invention.
• the calcium-containing compound used in a process according to the invention is a physiologically tolerable calcium-containing compound that is therapeutically and/or prophylactically active.
• Calcium is essential for a number of key functions in the body, both as ionized calcium and a calcium complex (Campell AK. Clin Sci 1987; 72:1-10). Cell behaviour and growth are regulated by calcium. In association with troponin, calcium controls muscle contraction and relaxation (Ebashi S. Proc R Soc Lond 1980; 207:259-86).
• Calcium selective channels are a universal feature of the cell membrane and the electrical activity of nerve tissue and the discharge of neurosecretory granules are a function of the balance between intracellular and extra cellular calcium levels (Burgoyne RD. Biochim Biophys Acta 1984;779:201-16). The secretion of hormones and the activity of key enzymes and proteins are dependent on calcium. Finally calcium as a calcium phosphate complex confers rigidity and strength on the skeleton (Boskey AL. Springer, 1988:171-26). Because bone contains over 99% of the total body calcium, skeletal calcium also serves as the major long-term calcium reservoir.
• Calcium salts such as, e.g., calcium carbonate is used as a source of calcium especially for patients suffering from or at risk of osteoporosis. Moreover, calcium carbonate is used as an acid-neutralizing agent in antacid tablets.
• osteopenia affects cancellous bone more than cortical bone and may not be completely reversible with calcium supplementation. If the animal is growing reduced calcium intake leads to stunting. In the premature human neonate the higher the calcium intake, the greater the increase in skeletal calcium accretion which, if high enough, can equal gestational calcium retention. During growth chronic calcium deficiency causes rickets. Calcium supplements in both pre- and postpubertal healthy children leads to increased bone mass. In adolescents the higher the calcium intake, the greater the calcium retention, with the highest retention occurring just after menarche.
• Calcium supplementation reduces the rate of age-related bone loss (Dawson- Hughes B. Am J Clin Nut 1991 ;54:S274-80).
• Calcium supplements are important for individuals who cannot or will nor achieve optimal calcium intakes from food. Furthermore, calcium supplement is important in the prevention and treatment of osteoporosis etc.
• ASA acetylsalicylic acid
• NSAIDS nonsteroidal anti-inflammatory drugs
• Calcium salts like e.g. calcium carbonate is used in tablets and due to the high dose of calcium required, such tablets are often in the form of chewable tablets. It is a challenge to formulate e.g. chewable tablets containing a calcium salt, which tablets have a pleasant taste and an acceptable mouth feel without the characteristic dominating taste or feeling of chalk.
• a calcium-containing compound for use according to the invention may be e.g.
• calcium sources may be water-soluble calcium salts, or complexes like e.g. calcium alginate, calcium-EDTA and the like or organic compounds containing calcium like e.g. calcium organophosphates. Use of bone meal, dolomite and other unrefined calcium sources is discouraged because these sources may contain lead and other toxic contaminants. However, such sources may be relevant if they are purified to a desired degree.
• the calcium-containing compound may be used alone or in combination with other calcium-containing compounds.
• a dosage form made according to the invention contains an amount of the calcium-containing compound corresponding to from about 100 to about 1000 mg Ca such as, e.g., from about 150 to about 800 mg, from about 200 to about 700 mg, from about 200 to about 600 mg or from about 200 to about 500 mg Ca.
• Calcium carbonate can be in three different crystal structures: calcite, aragonite and vaterite. Mineralogically, these are specific mineral phases, which relate to the distinct arrangement of the calcium, carbon and oxygen atoms in the crystal structure. These distinct phases influence the shape and symmetry of the crystal forms.
• calcite is available in four different shapes: scalenohedral, prismatic, spherical and rhombohedral, and aragonit crystals can be obtained as e.g. discrete or clustered needle-like shapes. Other shapes are also available such as, e.g., cubic shapes (Scoralite 1A + B from Scora).
• a suitable quality of calcium carbonate is calcium carbonate having a mean particle size of 60 ⁇ m or less such as, e.g., 50 ⁇ m or less or 40 ⁇ m or less.
• an interesting quality of calcium carbonate has a bulk density below 2 g/mL.
• Calcium carbonate 2064 Merck (available from Merck, Darmstadt, Germany) that has a mean particle size of 10 - 30 ⁇ m, an apparent bulk density of 0.4 to 0.7 g/mL, and a specific surface area of 0.3 m2/g;
• Calcium carbonate 2069 Merck (available from Merck, Darmstadt, Germany) that has a mean particle size of approx. 3.9 ⁇ m, and an apparent bulk density of 0.4 to 0.7 g/mL;
• Scoralite 1A (available from Scora Watrigant SA, France) has a mean particle size of 5 to 20 ⁇ m, an apparent bulk density of 0.7 to 1.0 g/mL, and a specific surface area of 0.6 m2/g;
• Scoralite 1 B (available from Scora Watrigant SA, France) has a mean particle size of 10 -25 ⁇ m, an apparent bulk density of 0.9 to 1.2 g/mL, and a specific surface area of 0.4 to 0.6 m2/g;
• Scoralite 1A + B (available from Scora Watrigant SA, France) have a mean particle size of 7 - 25 ⁇ m, an apparent bulk density of 0.7 to 1.2 g/mL, and a specific surface area of 0.35 to 0.8 m2/g;
• Pharmacarb LL (available from Chr. Hansen, Mahawah New Jersey) L has a mean particle size of 12 - 16 ⁇ m, an apparent bulk density of 1.0 to 1.5 g/mL, and a specific surface area of 0.7 m2/g; Sturcal L, Sturcal H, Sturcal F and Sturcal M (available from Specialty Minerals, Bethlehem, Pensylvania); Sturcal L has a mean particle size of approx. 7 ⁇ m, an apparent bulk density of 0.78 to 0.96 g/mL, Sturcal L consists of scalenohedral shaped crystals;
• Sturcal H has a mean particle size of approx. 4 ⁇ m, an apparent bulk density of 0.48 to 0.61 g/mL;
• Sturcal F has a mean particle size of approx. 2.5 ⁇ m, an apparent bulk density of 0.32 to 0.43 g/mL;
• Sturcal M has a mean particle size of 7 ⁇ m, an apparent bulk density of 0.7 to 1.0 g/ mL, and a specific surface area of 1.0 m2/g;
• Mikhart 10 has a mean particle size of 10 ⁇ m
• Mikhart SPL has a mean particle size of 20 ⁇ m
• Mikhart 15 has a mean particle size of 17 ⁇ m
• Mikhart 40 has a mean particle size of 30 ⁇ m, an apparent bulk density of 1.1 to 1.5 g/mL;
• Mikhart 65 has a mean particle size of 60 ⁇ m, an apparent bulk density of 1.25 to 1.7 g/mL;
• Omyapure 35 (available from Omya S.A.S, Paris, France) has a mean particle size of 5 - 30 ⁇ m, and a specific surface area of 2.9 m 2 /g;
• Socal P2PHV (available from Solvay, Brussels, Belgium) has a mean particle size of 1.5 ⁇ m, an apparent bulk density of 0.28 g/mL, and a specific surface area of 7.0 m 2 /g;
• Calci Pure 250 Heavy, Calci Pure 250 Extra Heavy and Calci Pure GCC HD 212 with a mean particle size of 10-30 ⁇ m, an apparent bulk density of 0.9 - 1.2 g/ml, and a specific surface area of 0.7 m 2 /g (available from Particle Dynamic Inc., St. Louis Montana).
• the content of the calcium-containing compound in a tablet made according to the present invention is in a range from about 40% to about 100% w/w such as, e.g., from about 45% to about 98% w/w, from about 50% to about 95% w/w, from about 55% to about 90% w/w or at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w.
• the dose of calcium for therapeutic or prophylactic purposes is from about 350 mg (e.g. newborn) to about 1200 mg (lactating women) daily.
• the amount of the calcium-containing compound in the tablets can be adjusted to that the tablets are suitable for administration 1-4 times daily, preferably once or twice daily.
• the calcium-containing compound used in a process of the invention is calcium carbonate such as calcium carbonate mentioned above.
• a granulate or tablet made according to the invention may comprise a further therapeutically and/or prophylactically active substance, or it may contain one or more nutrients such as, e.g. one or more vitamins or minerals.
• nutrients such as, e.g. one or more vitamins or minerals.
• vitamins or minerals e.g. one or more vitamins or minerals.
• vitamin B vitamin C
• vitamin D vitamin D
• vitamin K minerals
• minerals like e.g. zink, magnesium, selenium etc.
• D-vitamin compounds such as, e.g., Vitamin D 2 (ergocalciferol) and Vitamin D 3 (cholecalciferol) including dry vitamin D 3 , 100 CWS available from Roche and dry vitamin D 3 100 GFP available from BASF.
• vitamin D In addition to its action on calcium and skeletal homeostasis, vitamin D is involved in the regulation of several major systems in the body.
• the actions of vitamin D are medicated at the genome by a complex formed by 1 ,25-(OH) 2 vitamin D mainly produced in the kidney, with the vitamin D receptor (VDR).
• VDR vitamin D receptor
• the 1 ,25-(OH) 2 vitamin D/VDR complex has important regulatory roles in cell differentiation and in the immune system. Some of these actions are probably dependant on the ability of certain tissues other than the kidney to produce 1 ,25-(OH) 2 vitamin D locally and act as a paracrine (Adams JS et al. Endocrinology 1996; 137:4514-7).
• Vitamin D insufficiency the preclinical phase of vitamin D deficiency, also causes a reduced calcium supply and secondary hyperparathyroidism, albeit of a milder degree than found with deficiency. If this state remains chronic, osteopenia results.
• the biochemical process underlying this state of calcium insufficiency is probably inappropriate level of 1 ,25-(OH) 2 vitamin D due to a reduction in its substrate 25-OHD (Francis RM et al. Eur J Clin Invest 1983; 13:391-6).
• the state of vitamin D insufficiency is most commonly found in the elderly. With age there is a decrease in serum 25-OH vitamin D due to decreased sunlight exposure and possible to decreased skin synthesis.
• RDA Recommended Daily Allowance
• Vitamin D is very sensitive towards humidity and is subject to degradation. Therefore, vitamin D is often administered in a protective matrix. Accordingly, when tablets are prepared containing a vitamin D it is of utmost importance that the compression forces applied during the tabletting step do not decrease the protective effect of the matrix and thereby impair the stability of vitamin D. To this end, the combination of the various ingredients in a granulate or tablet made according to the invention has proved to be very suitable in those cases where vitamin D also is incorporated into the composition as it is possible to employ a relatively low compression force during tabletting and still achieve a tablet with suitable mechanical strength (crushing strength, friability etc.). Other active ingredients
• Isoflavones examples include isoflavones, vitamin K, vitamin C, vitamin B6 and oligosaccharides such as inulin and oligofructose.
• Isoflavones exhibit a weak oestrogenic effect and can thus increase bone density in post-menopausal women.
• Isoflavones are available under the trade name Novasoy 400 from ADM Nutraceutical, Illinois, USA. Novasoy 400 contains 40% isoflavones and will typically be used in an amount sufficient to provide 25 to 100 mg isoflavone/dosage.
• Isoflavones may be included in the second granulate; however as Novasoy 400 is a relatively cohesive powder it is preferred that it be included in the first granulate in order to ensure that it is uniformly distributed.
• Vitamin K (more especially vitamin K 1 ) may improve biochemical markers of bone formation and bone density and low concentrations of vitamin K, have been associated with low bone mineral density and bone fractures.
• Vitamin K is available from Roche as Dry Vitamin K, 5% SD, a dry substance containing 5% vitamin K 1 .
• vitamin K will be used in a quantity sufficient to provide 0.05 to 5 mg vitamin K ⁇ dosage.
• Vitamin C and vitamin B6 (available from Roche, Takeda and BASF amongst others) function as co-factors in the formation of collagen, the main component of the organic matrix of bone. Vitamin C and vitamin B6 will typically be used in quantities sufficient to provide 60 to 200 mg vitamin C/dosage and1.6 to 4.8 mg vitamin B6/dosage respectively.
• Oligosaccharides have been shown to facilitate and increase calcium absorption and may typically be used in quantities sufficient to provide 0.3 to 5 g oligosaccharide/dosage. In general it is desirable that a total of at least 5g oligosaccharide is administered daily to facilitate calcium uptake and to obtain a pre- biotic effect.
• an active component which forms a minor part of the overall granulate, e.g. vitamin D
• the invention provides a tablet comprising i) a calcium-containing compound as an active substance, ii) a vitamin D, and iii) optionally one or more pharmaceutically acceptable excipients. More specifically, the tablet may comprise i) at least 200 mg of the calcium-containing compound (normal range 200-1500 mg),
• ii) at least 5 ⁇ g of vitamin D (normal range 5-100 ⁇ g - 1 ⁇ g 40 IU), and iii) optionally one or more pharmaceutically acceptable excipients.
• the invention provides a tablet comprising i) from about 50% to about 90% w/w of the calcium-containing compound, ii) from about 0.00029%o about 0.0122 w/w of a vitamin D, and iii) optionally one or more pharmaceutically acceptable excipients with the proviso that the total amount of ingredients corresponds to about 100% w/w.
• the tablet may comprise i) from about 50% to about 90% w/w of the calcium-containing compound, ii) from about 5 to about 30% w/w of a sweetening agent, iii) from about 0.12% to about 4.9 % w/w of a vitamin D including a protective matrix, as delivered by supplier. iv) optionally one or more pharmaceutically acceptable excipients with the proviso that the total amount of ingredients corresponds to about 100% w/w.
• the process according to the invention may also comprise compression of a particulate material obtained as described herein optionally in admixture with one or more pharmaceutically acceptable excipients.
• tablets can be prepared by any suitable process known to a person skilled in the art.
• a person skilled in the art will know how to employ the different techniques optionally with guidance from Remington's The Science and Practice of Pharmacy
• the amount of the calcium-containing compound in a tablet corresponds to from about 100 to about 1000 mg Ca such as, e.g., from about 150 to about 800 mg, from about 200 to about 700 mg, from about 200 to about 600 mg or from about 200 to about 500 mg Ca.
• pharmaceutically acceptable excipient is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se.
• a pharmaceutically acceptable excipient may be added to the active drug substance with the purpose of making it possible to obtain a pharmaceutical composition, which has acceptable technical properties.
• the calcium-containing compound is normally admixed with one or more pharmaceutically acceptable excipients before compression into tablets.
• excipients include those normally used in formulation of solid dosage forms such as, e.g. fillers, binders, disintegrants, lubricants, flavouring agents, colouring agents, including sweeteners, pH adjusting agents, buffering agents, stabilizing agents, etc.
• excipients suitable for use in a tablet prepared according to the present invention are given examples of excipients suitable for use in a tablet prepared according to the present invention.
• sweeteners examples include dextrose, erythritol, fructose, glycerin, glucose, inositol, isomalt, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, etc..
• Sorbitols e.g. Neosorb P100T, Sorbidex P166B0 and Sorbogem Fines Crystalline Sorbitol available from Roquette Freres, Cerestar and SPI Polyols Inc. respectively.
• Maltisorb P90 (maltitol) available from Roquette Freres, Xylitol CM50, Fructofin CM (fructose) and Lactitol CM50 available from Danisco Sweeteners, Isomalt ST-PF, Gaio Tagatose and Manitol available from Palatinit, ArIa Foods and Roquette, Freres respectively.
• Sorbitol has a sweetening effect (compared to sucrose) of 0.55; maltitol that has a sweetening effect of ⁇ 1 ; xylitol that has a sweetening effect of 1 , isomalt that has a sweetening effect of ⁇ 0.5, etc.
• the sweetening effect may be of value in connection with choosing the individual sweetening agents. Thus, if a decreased tablet weight and volume are desired, it is suitable to choose a sweetening agent having a high sweetening effect.
• cyclamate salt e.g. calcium cyclamate, sodium cyclamate
• neohesperidine dihydrochalcone neohesperidine hydrochloride
• saccharin e.g. ammonium saccharin, calcium saccharin, potassium saccharin, sodium saccharin
• sucralose e.g. ammonium saccharin, calcium saccharin, potassium saccharin, sodium saccharin
• Alginic acid - alginates carboxymethylcellulose calcium, carboxymethylcellulose sodium, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose derivatives such as low-substituted hydroxypropylcellulose (e.g LH 11 , LH 20, LH 21 , LH 22, LH 30, LH 31 , LH 32 available from Shin-Etsu Chemical Co.) and microcrystalline cellulose, polacrilin potassium or sodium, polyacrylic acid, polycarbofil, polyethylene glycol, polyvinylacetate, polyvinylpyrrolidone (e.g.
• Polyvidon® CL Polyvidon® CL, PoIy- vidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); sodium car- boxymethyl starch (e.g. Primogel® and Explotab®), sodium croscarmellose (i.e. cross- linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®), sodium starch glycolate, starches (e.g potato starch, maize starch, rice starch), pre-gelatinised starch.
• Primogel® and Explotab® sodium croscarmellose (i.e. cross- linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®)
• sodium starch glycolate starches (e.g potato starch, maize starch, rice starch), pre-gelatinised starch.
• the disintegrant used preferably results in the disintegration of the tablet within 30 minutes, more preferable within 15 min, most preferable within 5 min.
• a somewhat longer disintegration time is allowed.
• Effervescent agent e.g. mixture of sodium hydrogen carbonate (carbonates, alkaline, alkaline earth metals) and citric acid (tartaric acid, fumaric acid etc.)
• Glidants and lubricants may be incorporated such as stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, hydrogenated vegetabable oils, colloidal silica, sodium stearyl fumarate, polyethylenglycols and alkyl sulphates.
• Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like.
• magnesium stearate is used.
• maltodextrins e.g. Lodex® 5 and Lodex® 10
• dextrose fructose, glucose, inositol, erythritol, isomalt
• lactitol lactose (e.g., spray-dried lactose, ⁇ -lactose, ⁇ - lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast-Floe®)
• maltitol maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol
• low- substituted hydroxypropylcellulose e.g LH 11 , LH 20, LH 21 , LH 22, LH 30, LH 31 , LH 32 available from Shin-Etsu Chemical Co.
• microcrystalline cellulose e.g., various grades of Avicel®, such as Avicel® PH101 , Avicel
• calcium hydrogen phosphate calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate), calcium sulphate, carboxyalkylcellulose, dextrates, dibasic calcium phosphate, gelatine, gummi arabicum, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium carbonate, magnesium chloride, methylcellulose, polyethylene glycol, polyethylene oxide, polysaccharides e.g. dextran, soy polysaccharide, sodium carbonate, sodium chloride, sodium phosphate.
• calcium phosphate e.g. basic calcium phosphate, calcium hydrogen phosphate
• calcium sulphate carboxyalkylcellulose, dextrates, dibasic calcium phosphate, gelatine, gummi arabicum, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium carbonate, magnesium chloride, methylcellulose, polyethylene glycol, polyethylene oxide, polysaccharides e.g. dextran, soy polysaccharide,
• Surfactants/enhancers may be employed such as Non-ionic (e.g., polysorbate 20, polysorbate 21 , polysorbate 40, polysorbate 60, polysorbate 61 , polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalkohol),
• Non-ionic e.g., polysorbate 20, polysorbate 21 , polysorbate 40, polysorbate 60, polysorbate 61 , polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate,
• anionic e.g., docusate sodium and sodium lauryl sulphate
• cationic e.g., benzalkonium chloride, benzethonium chloride and cetrimide.
• Fatty acids, fatty alcohols and fatty esters for example: ethyl oleate, sodium oleate, lauric acid, methyl laurate, oleic acid, sodium caprate
• bile salts for example: sodium deoxycholate, deoxycholic acid, sodium cholate, cholic acid, sodium glycocholate, sodium glycodeoxycholate, sodium taurocholate, sodium taurodeoxycholate;
• cytoadhesives for example: lectins (e.g. Lycopersicon Esculentum Agglutinin, Wheat Germ Agglutinin, Urtica Dioica Agglutinin).
• lectins e.g. Lycopersicon Esculentum Agglutinin, Wheat Germ Agglutinin, Urtica Dioica Agglutinin.
• N-acylated amino acids especially N-[8-(2-hydroxy-4-methoxy)benzoyl]amino caprylic acid (4-MOAC), 4-[4-(2-hydroxybenzoyl)amino]butyric acid, sodium N-[8-(2- hydroxybenzoyl)amino]-caprylate);
• phospholipids for example: hexadecylphosphocholine, dimyristoylphosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, 1 ,2-di(2,4-octadecadienoyl)-sn-glycerol-3-phosphorylcholine and phosphatidylcholines (e.g. didecanoyl-L-phosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine), lysophosphatidylcholine is of particular interest;
• cyclodextrins for example: ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin, methyl cyclodextrin; especially dimethyl- ⁇ -cyclodextrin is of particular interest;
• fusidic acid derivatives for example: sodium taurodihydrofusidate, sodium glycodihydrofusidate, sodium phosphate- dihydrofusidate; especially sodium taurodihydrofusidate is of particulare interest;
• n-lauryl-beta-D-maltopyranoside is of particular interest, alpha 1000 peptide, peptide MW ⁇ 1000 comprising at least 6 mol% of aspartatic- and glutamic Acid, decomposed royal jelly, prebiotica, butyrate, butyric acid, vitamin D 2 , vitamin D 3 , hydroxy-vitamin D 3 , 1.25-dihydroxy-vitamin D 3 , spirulina
• the dosage form may be provided with a coating.
• Hydrofilic film formers such as hydroxypropylmethylcellulose (HPMC) (e.g. HPMC E5, HPMC E15), hydroxyethylcellulose, hydroxypropylcellulose, polydextrose and maltodextrin,
• Film additives Acetylated monoglyceride, acetyltributyl, acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, calcium stearate, castor oil, cetanol, chlorebutanol, colloidal silica dioxide, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl maleate, diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl sebacate, diethyl succinate, dimethylphthalate, dioctyl phthalate, glycerin, glyceroltributyrate, glyceroltriacetate, glyceryl behanate, glyceryl monostearate, hydrogenated vegetable oil, lecithin, leucine, magnesium silicate, magnesium stearate, polyethylene glycol, prop
• Granulation liquids containing 10, 15, 20, 26 and 33% polyvinylpyrrolidone (PVP) were used for the trials.
• the trials had the following objectives:
• the three processing parameters to be varied with a high and low value according to the design were the PVP concentration, granulation temperature (i e. the temperature in the first two inlet air compartments) and the spray rate. Relatively wide processing windows were chosen in order to achieve detectable differences for the response variables.
• the response variables were the moisture content, particle size/ distribution and bulk density. These are the important granule characteristics for the subsequent blending and tableting properties.
• the in-process requirement for the moisture content is set to a maximum of 0.35% due to problems, which occasionally arises due to local over wetting in the fluid bed. This problem is probably due to a poor fluidisation in the batch fluid bed with resultant sticking of the granulate to the walls of the product container.
• the particle size/distribution, bulk density and moisture content were measured after each trial. Generally a finer granulate was produced with a raspberry shaped surface as opposed to the more round shaped granules from a vertical fluid bed. The granules from the horizontal fluid bed thus create a more expanded bed with a resultant decrease in the bulk density.
• Table 2 Granulate characteristics from example 1 and batch 1 to 15
• Moisture content The results for the moisture content show values well below the in process requirement of maximum 0.35%. Only one granulate is over wetted (H3001-2) and the reason being that this batch received the highest spray load at the lowest temperature with a PVP concentration of 33% in the granulation liquid.
• Bulk density The mean value for the bulk density was 0.71 g/ml. This is about 15% less than that obtained from a batch fluid bed with the same composition for the granulate employed in the two cases. The reason is that the granulate from the continuous fluid bed has been less subjected to frictional forces and thus show a more expanded structure with a resultant low value for the bulk density.
• Particle size/distribution The results from the sieve analysis show granulates that are generally too fine where 8 of the batches are out of specification with respect to the fine size fraction below 125 ⁇ m. The Malvern results also confirm this where the mean particle size for the 15 granulates is 136 ⁇ m. This is somewhat lower when compared to the mean particle size from a batch fluid bed, which is in the range of 200 - 250 ⁇ m.
• the granules from the continuous fluid bed process are characteristically more irregular in shape as these have not been exposed to the same friction and gravitational forces that are present in a batch process.
• the two pictures with the largest magnification show that the binding mechanism is the same between the two technologies.
• the fine strands of PVP can be seen to bind the cubic shaped crystals of calcium carbonate together in an interlocking mesh.
• This homogenous distribution of the binder also explains the excellent consolidation properties of the granulate during tablet compression.
• the inlet temperature can be set to a high level in order to optimize the drying capacity of the continuous process.
• a sensoric evaluation was carried out by a panel of 7 qualified persons.
• Batch PU30305 with a low bulk density and PU30306 with a high bulk density from the constituent Heinen calcium granulate was tested against a reference based on the fluid bed batch wise calcium granulate (PU30307).
• the two batches based on the Heinen granulates were tested against the reference by a paired test with respect to orange flavour and hardness.
• the sensoric panel did not detect any significant difference at a 5% level between the samples in each case.
• Example 2 (batch 16-21) The trials carried out at the Glatt facility in Dresden had the following objectives:
• Table 3 Granulate characteristics for granulates produced with Glatt GF 20
• Moisture content and bulk density The results for both the moisture content and bulk density show a very good reproducibility with values well inside the specified requirements.
• the values for the bulk densities are higher than the results from the Heinen trials. This is most likely because the particle size of the granulates from the Glatt trials are finer with a resultant denser packing tendency for granulates.
• Particle size/distribution There is a good correlation between the Malvern results and the sieve analysis.
• the value for the mean particle size varies very little except for the last batch where the mean value is increased from approximately 125 ⁇ m to 143 ⁇ m.
• the size fraction between 450 and 125 ⁇ m is too small and the size fraction below 125 ⁇ m is too big.
• the reason for the relatively small value for the mean particle size was that the process was carried out with processing conditions, which favoured "dry conditions". Further optimisation including increasing the spray load would have been necessary in order to increase the value for the mean particle size.
• Bottom spray The trials showed that bottom spray could be effectively used to produce granulates, which was the aim for this set of trials.
• the trials were carried out with an inlet air humidity of 8 g H 2 O/kg air as opposed to the inlet air humidity for the batches in example 1 , which was 4 g H 2 O/kg air. This difference caused an increase in the relative humidity inside the granulation processing compartments, which again increased the agglomeration capacity when compared to the conditions during the trials reported in Example 1.
• Table 5 Granulate characteristics for trials from example 3
• Moisture content and bulk density The results for the moisture measurements and bulk density were all inside the requirements and very similar to the results achieved from the trials in example 1.
• Batch 1 A and 2A are produced with the same set points for the processing parameters as H2901-1 and H2901-2 (table 1 and 2), yet there is a significant difference in the particle size between the two pairs of batches.
• the particle size given as D 10 , D 50 and D 90 are 26, 130, 312 ⁇ m for batch H2901-1/H2901-2 and 44, 180, 417 ⁇ m for batch 1 A/2A.
• the big difference in the inlet air moisture content explains the difference in the particle size between the granulates produced during the two test periods.
• the product temperatures for the batches run at 60/60/80 0 C in example 1 and in the present example are 45.8 and 40.8 0 C 1 respectively, which are equivalent to relative moisture contents in the processing chamber of 16 and 29%.
• the Heinen CFB granulates were produced on three different occasions and with the same set of processing conditions as specified under the respective examples. From the table it can be seen that the particle size distribution is more narrow for the CFB granulates when compared to the results from the batch fluid beds. The narrow particle size distribution for the CFB granulates is shown by the low result for the span value. A more narrow size distribution for the CFB batches is also exemplified by the lower value for D 90 with a reduction in the course fraction of approximately 20-25% when comparing batch series with approximately the same mean particle size.
• the moisture load is here defined as the combined moisture effect of the inlet air humidity and the spray load (spray rate at a certain concentration of PVP).
• the PVP concentration has been plotted against the mean particle size from the Malvern analysis in figure 9.
• the plotted results inside the two loops all contain the nominal or correct amount of 2.2% PVP whereas the PVP concentrations for the other batches are either higher or lower than this value.
• the experiments have been carried out at two different times in week 5/2003 and 32/2003 where the absolute moisture contents in the inlet air were 2.9 and 7.5 g/m 3 respectively.
• Two batches (H3001-5 and -6) are produced with 26% PVP concentration in the granulation liquid and with a spray rate of 106 g/min where the granulation inlet temperature differ by 1O 0 C between the two batches.
• the mean particle size has been reduced to approximately 120 ⁇ m.
• Spray load is here defined as the amount of moisture in the spray rate.
• a spray rate of 83 g/min and a PVP content of 33% are thus giving the lowest spray load among the trials in the experimental design. At this PVP concentration and spray rate it seems that the spray load is insufficient in order to achieve a satisfactory agglomeration.
• the largest particle size is seen for the highest spray rate of 205 g/min but this also contain as much as 5.5% of PVP in the granulate. At this spray rate the spray load is sufficient and in combination with an increased PVP content this ensures an increased agglomeration capacity.
• Feed rate of powder mixture 75 kg/h
• Table 7 Particle size distribution, bulk density and moisture content for 6 samples of continuous fluid bed calcium granulate
• the bulk densities for the samples taken from the big-bags during the continuous granulation process are typically low in value.
• the bulk density is increased up to a level which is comparable to the bulk density for a granulate based on a batch process.
• Particle size/distribution The major proportion of the granulates are inside the size fraction of 425 to 125 ⁇ m where as only a small size fraction is below 125 ⁇ m.
• the mean particle size is only reduced from 246 to 234 ⁇ m after the completion of the mixing process which shows that the granulate mixture can withstand the mixing process in a satisfactory fashion.
• the reproducibility of the particle size and distribution for the six samples of granulate from the continuous granulation process is depicted in figure 7 which show the Malvern analysis for the samples.
• the tablets were automatically transferred to a packaging machine and packed into 275 ml tablet containers.
• Example 5 (batch 31-42) The set of trials had the following objectives: • To show reproducible results with respect to granulate characteristics in a long term trial period.
• the same set of processing parameters for the continuous granulation process was used as described for example 4.
• the granulation process was run for 13 hours in order to produce a sufficient amount of calcium granulate for the mixing trials and to show reproducibility as given in the below table.
• Table 8 Particle size distribution and bulk density for 7 samples of continuous fluid bed calcium granulate
• the four batches were produced with a granulation spray rate of 187.5 g/min and two trials with a high and low spray load respectively were carried out at two inlet granulation temperatures as shown above. The four trials proceeded satisfactory giving rise to calcium granulates with characteristics as shown below.
• Table 10 Particle size distribution and bulk density for granulates with a low and high spray load
• the particle size can be controlled by the spray load and that this control is most effectively executed at an inlet granulation temperature of 8O 0 C.
• the results show a control of the mean particle size in a range of going from 100 to 300 ⁇ m.
• the change of raw material qualities was carried out without interrupting the infeed or the set-points for process parameters. A small reduction in the feed rate was noted due to the reduced bulk density of the Merck quality, which affected the volumetric dosing of the raw material preblend.
• Table 11 Granulate characteristics for calcium granulate with Merck 102064
• the calcium granulate was used in order to produce three mixing batches each containing 230 kg of granulate.
• the mean particle sizes before mixing for the three batches were 217, 203 and 252 ⁇ m respectively.
• the Ruberg 400 mixer is a twin shaft vertical low shear mixer with forced convection and with an effective mixing volume of 320 litres (80%).
• the batch size for the three batches was 238.52 kg. All the ingredients except for magnesium stearate were charged into the mixer and blended for 4 min at 50 RPM, magnesium stearate was added and mixed for an additional 1 min.
• Three 3 kg samples were taken as samples during the discharge of the mixer: At the start of the discharge, in the middle and the end of discharge. The three separate samples for each batch were made into 16 mm normal convex shaped tablets and a representative sample of 10 tablets taken out for the three lots of tablets to be analyzed with respect to the content of vitamin D 3 .
• the results for the content uniformity with respect to vitamin D 3 as IU (international units) for the three batches of calcium chewable tablets are shown in the below table:
• Table 12 Uniformity of content for vitamin D 3 for three batches of calcium chewable tablets with 20 ⁇ g vitamin D 3
• the two most important considerations concerning the particle size and distribution of the calcium granulate are related to the homogeneity of the distribution of vitamin D 3 and the tableting properties of the final tableting mixture.
• the mean particle size of the sieved vitamin D 3 is in the region of 180-200 ⁇ m and the aim is to get the mean particle size reduced to approximately 150-180 ⁇ m in order to improve the homogeneity of vitamin D 3 even further.
• the decrease in the particle size for vitamin D 3 is beneficial because of the resultant increase in the number of vitamin D 3 particles per dosage unit, which ensures a more even distribution of vitamin D 3 .
• Heinen granulates are well suited to match the particle size and distribution of the vitamin D 3 .
• Segregation problems in the final tableting mixture may occur when the coarse size fraction in the tableting mixture increases. This may occur as a function of vibration during handling or uneven flow in the IBC containers during the tableting step. In this respect it would have been desirable to reduce the coarse fraction in the FB batch wise granulate.
• Heinen granulates contain a much smaller coarse fraction compared to granulates from a batch process and are thus better suited with respect to the blending efficiency and prevention of subsequent segregation.
• Reference example 1 The same composition of the preblend of calcium carbonate and sorbitol as described under “materials end methods" was used in the following qualification trials with calcium carbonate, Merck 102064.
• the qualification trials were run on an Aeromatic size 6 batch fluid bed with a batch size of 250 kg.
• the most important process parameters controlling the agglomeration process in a batch fluid bed are the inlet air temperature, spray rate and inlet air humidity.
• the existing set-points based on the granulation of Scoralite 1A+1 B were 5O 0 C and 720 g/ml for the inlet air granulation temperature and spray rate respectively.
• the inlet air humidity was ambient according to the weather conditions from the outside air. Variations in the inlet air humidity were compensated by adjusting the PVP concentration and thus keeping the moisture load constant during the trials.
• Control of mean particle size and distribution The trials have shown that the mean particle size can be effectively controlled in a particle size window ranging from 100 to 300 ⁇ m and with a narrow size distribution documented by a low span values. This control over the mean particle size and the same time keeping a narrow size distribution facilitates a perfect matching of the calcium granulate to the mean particle size and distribution for a low amount of vitamin D 3 in the secondary granulate. The perfect matching of the two components during the blending step is documented by the good homogeneity of vitamin D 3 in the resultant chewable calcium tablets.
• the continuous fluid bed process have been show to be much more robust in several aspects connected to the granulation and drying of a calcium granulate as opposed to the batch process.
• the continuous fluid bed process is more robust with respect to processing difficulties like clogging of powder on to product container screen, walls in the product container and expansion chamber and, clogging of exhaust air filters.
• the continuous process is not sensitive to batch to batch variations due to frequent changes in the set-points for the critical processing parameters and is also less susceptible to changes in the inlet air moisture compared to a batch process. Finally it has been shown that the continuous process is much more robust to changes in the physical characteristics of calcium-containing compound.

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